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(12) United States Patent (10) Patent No.: US 7.452,861 B2 Kaniga (45) Date of Patent: Nov

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(12) United States Patent (10) Patent No.: US 7.452,861 B2 Kaniga (45) Date of Patent: Nov USOO7452861 B2 (12) United States Patent (10) Patent No.: US 7.452,861 B2 Kaniga (45) Date of Patent: Nov. 18, 2008 (54) USE OF AN ECHINOCANDIN ANTIFUNGAL Chiou et al., “Synergy, Pharmacodynamics, and Time-Sequenced AGENT IN COMBINATION WITH A Ultrastructural Changes of the Interaction between Nikkomycin Z. GLYCOPEPTIDE ANTIBACTERAL AGENT and the Echinocandin FK463 against Aspergillus filmigatus'. Anti microbial Agents and Chemotherapy, vol. 45, No. 12, pp. 3310-3321 (75) Inventor: Koné Kaniga, Hayward, CA (US) (2001). Denning, "Echinocandins:a new class of antifungal'. Journal of Anti (73) Assignee: Theravance, Inc., South San Francisco, microbial Chemotherapy, 49, pp. 889-891 (2002). CA (US) Denning, "Echinocandin antifungal drugs'. The Lancet, vol. 362, pp. (*) Notice: Subject to any disclaimer, the term of this 1142-1151 (2003). patent is extended or adjusted under 35 Eliopoulos et al., “Antimicrobial Combinations'. Antibiotics in U.S.C. 154(b) by 486 days. Laboratory Medicine, 4th Edition, Williams & Wilkins, pp. 330-396 (1996). (21) Appl. No.: 10/895.492 Groll et al., "Caspofungin: pharmacology, safety and therapeutic potential in Superficial and invasive fungal infections'. Expert Opin. (22) Filed: Jul. 21, 2004 Investig. Drugs, 10(8), pp. 1545-1558 (2001). Hossain et al., “New investigational antifungal agents for treating (65) Prior Publication Data invasive fungal infections'. Expert Opin. Invest. Drugs, 9(8), pp. US 2005/OO26819 A1 Feb. 3, 2005 1797-1813 (2000). Lewis et al., “Rationale for Combination Antifungal Therapy'. Related U.S. Application Data Pharmacotherapy, vol. 21, No. 8, pp. 149s-164s (2001). Manavathu et al., “Differential activity of triazoles in two-drug com (60) Provisional application No. 60/489,173, filed on Jul. binations with the echinocandin caspofungin against Aspergillus 22, 2003. fumigatus”. J. of Antimicrobial Chemotherapy, 51, pp. 1423-1425 (2003). (51) Int. Cl. Nicolaou et al., “Chemistry, Biology, and Medicine of the A6 IK 38/16 (2006.01) Glycopeptide Antibiotics”. Angew. Chem. Int. Ed., 38, pp. 2096 A6 IK 38/00 (2006.01) 2152 (1999). A63I/33 (2006.01) Shalit et al., “In Vitro Synergy of Caspofungin and Itraconazole AOIN 43/00 (2006.01) against Aspergillus spp. MIC versus Minimal Effective Concentra (52) U.S. Cl. ................................ 514/8: 514/183: 514/9 tion End Points'. Antimicrobial Agents and Chemotherapy, vol. 47. (58) Field of Classification Search ....................... None No. 4, pp. 1416-1418 (2003). See application file for complete search history. Sugar, "Overview: Antifungal combination therapy”, Current Opin (56) References Cited ion in Investigational Drugs, 2(10), pp. 1364-1365 (2001). Vanden Bossche, “Echinocandins-an update'. Expert Opin. Ther. U.S. PATENT DOCUMENTS Patents, 12(2), pp. 151-167 (2002). 5,378,804 A 1/1995 Balkovec et al. Lacroix, C., et al., "Echinocandins: a new class of antifungal agents'. 5,925,616 A 7, 1999 Whittemore Medicine et maladies infectieuses, 33(4): 183-191, Apr. 2003. (in 6,107,458 A 8, 2000 Ohki et al. French with English abstract). 6,267,979 B1* 7/2001 Raad et al. .................. 424/405 Link, H., “Antimicrobial prophylaxis and therapy in neutropenia'. 6,635,618 B2 10/2003 Leadbetter et al. Mycoses 46(Suppl. 2):21-32, Feb. 2003. (in German with English 6,719,991 B2 * 4/2004 Darouiche et al. .......... 424/422 abstract). 6,743,777 B1 6, 2004 Burkhardt et al. 2003, OO17975 A1 1/2003 Ikeda et al. (Continued) 2004/0242505 A1 12/2004 Kaniga 2005/0026819 A1* 2/2005 Kaniga .......................... 5148 Primary Examiner Cecilia J Tsang Assistant Examiner Marcela M Cordero Garcia FOREIGN PATENT DOCUMENTS (74) Attorney, Agent, or Firm Jeffrey A. Hagenah EP O 525.499 A1 2, 1993 EP O 667 353 A1 8, 1995 (57) ABSTRACT WO WOOOf72865 A2 12/2000 OTHER PUBLICATIONS This invention is directed to methods of administering an Ge et al. Vancomycin Derivatives That Inhibit Peptidoglycan echinocandin antifungal agent in combination with a glyco Biosynthesis Without Binding D-Ala-D-Ala. Sciene. Apr. 16, 1999. peptide antibacterial agent having a Substituent comprising at vol. 284, pp. 507-511.* Giglione et al. The situation on antimicrobial agents and chemo least about 8 carbon atoms. The invention is also directed to therapy in 2002: Highlights of the 42nd ICAAC. Sep. 27-30, 2002, methods of using an echinocandin antifungal agent in com San Diego, USA.Expert Opin. Ther. Targets. 2002. vol. 6 No. 6, pp. bination with a specified glycopeptide antibacterial agent to 691-697. treat fungal infections; and to compositions, kits and systems Boger. Vancomycin, Teicoplanin and Ramoplanin. Medicinal comprising an echinocandin antifungal agent and a specified Research Reviews. 2001. vol. 21, No. 5, pp. 356-381.* glycopeptide antibacterial agent. Arikan et al., “New agents for the treatment of systemic fungal infections-current status'. Expert Opin. Emerging Drugs, 7(1), pp. 3-32 (2002). 9 Claims, No Drawings US 7,452,861 B2 Page 2 OTHER PUBLICATIONS tobramycin and piperacillin: Effect on cyclosporine A-associated nephrotoxicity'. Antimicrobial Agents and Chemotherapy, vol. 35 Preobrazhenskaya, M. and Olsufyeva, E., “Patents on glycopeptides No. 11, pp. 2246-2252 (Nov. 1991). of the Vancomycin family and their derivatives as antimicrobials: Jan. Pace, John L., “TD-6424: A novel multifunctional antibiotic'. Abstr 1999-Jun. 2003”. Expert Opin. Ther: Patents, 14(2):141-173, 2004. Intersci ConfAntimicrob Agents Chemother; 42: Abstract No. 614. Taccone F.S., et al., Caspofungin Salvage therapy in a neutropenic Sep. 27-30, 2002. patient with probable invasive aspergillosis: a case report, Supportive Office Action in U.S. Appl. No. 10/854.575, dated Nov. 24, 2006. Care in Cancer. Official Journal of the Multinational Association of Office Action in U.S. Appl. No. 10/854.575, dated Apr. 27, 2007. Supportive Care in Cancer, 11(11):742-744, Nov. 2003. Office Action in U.S. Appl. No. 10/854.575, dated Aug. 6, 2007. Kureishi et al., “Double-blind comparison of teicoplanin versus vancomycin in febrile neutropenic patients receiving concomitant * cited by examiner US 7,452,861 B2 1. 2 USE OF AN ECHNOCANDIN ANTIFUNGAL In yet another of its method aspects, this invention provides AGENT IN COMBINATION WITH A a method for increasing the efficacy of an echinocandin anti GLYCOPEPTIDE ANTIBACTERAL AGENT fungal agent, the method comprising administering the echi nocandin antifungal agent to a subject in combination with a CROSS REFERENCE TO RELATED glycopeptide antibacterial agent having a substituent com APPLICATIONS prising at least about 8 carbon atoms. In one of its composition aspects, this invention provides a This application claims the benefit of U.S. Provisional pharmaceutical composition comprising: Application No. 60/489,173, filed on Jul. 22, 2003; the entire (a) an echinocandin antifungal agent; disclosure of which is incorporated herein by reference in its 10 (b) a glycopeptide antibacterial agent having a substituent entirety. comprising at least about 8 carbon atoms; and (c) a pharmaceutically acceptable carrier. BACKGROUND OF THE INVENTION In another aspect, this invention provides a kit comprising: (a) an echinocandin antifungal agent; and 1. Field of the Invention 15 (b) a glycopeptide antibacterial agent having a substituent This invention relates to the use of an echinocandin anti comprising at least about 8 carbon atoms. fungal agent in combination with a glycopeptide antibacterial In one embodiment, the kit further comprises instructions agent. More specifically, this invention relates to methods of for administering the antifungal and antibacterial agents to a using an echinocandinantifungal agent in combination with a Subject in need of treatment. glycopeptide antibacterial agent to treat fungal infections; In yet another aspect, this invention provides a system for and to compositions, kits and systems comprising an echi treating a fungal infection in a subject, the system compris nocandin antifungal agent and a glycopeptide antibacterial ing: agent. (a) an echinocandin antifungal agent; and 2. State of the Art (b) a glycopeptide antibacterial agent having a substituent Echinocandin antifungal agents, such as caspofungin, 25 comprising at least about 8 carbon atoms. micafungin and anidulafungin, are a relatively new class of This invention is also directed to the use of: therapeutic agents useful for treating fungal infections. Gen (a) an echinocandin antifungal agent; and erally, such echinocandin antifungal agents have been found (b) a glycopeptide antibacterial agent having a substituent to have fewer side effects than, for example, polyene antifun comprising at least about 8 carbon atoms; gal agents such as amphotericin B. However, numerous 30 in the manufacture of a medicament for the treatment of a adverse effects have been reported for echinocandin antifun fungal infection. gal agents including headache, fever, liver toxic effects, phle In particular, this invention is directed to the use of an bitis, histamine release, haemolysis and rash. See, for echinocandin antifungal agent in the manufacture of a medi example, Denning, "Echinocandin antifungal drugs. Lancet cament for administration in combination with a glycopep 2003; 362: 1142-51. 35 tide antibacterial agent having a Substituent comprising at Accordingly, a need exists for new methods of administer least about 8 carbon atoms for the treatment of a fungal ing echinocandin antifungal agents that reduce the side infection. effects of Such agents. In particular, a need exists for
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